Extrahepatic biliary atresia (BA) is a devastating disease of the neonate in which the hepatic and/or common bile duct is obliterated or interrupted. Infants and children with this diagnosis constitute 50-60% of the pediatric population that undergoes liver transplantation. However, there is still very little known about the pathogenesis of BA. Several recent observations have suggested that BA is not a single disease but rather a phenotype of several underlying specific disorders, each of which affects a subgroup of infants with the BA phenotype. For instance, there is a subgroup of infants with BA (approximately 20%) in which an abnormality in morphogenesis is likely because these infants also have visceral situs inversus. In a series of preliminary studies for this project we examined the possibility that the inv mouse, a transgenic mouse in which a recessive insertional disruption of the inv locus results in situs inversus and jaundice, is a mouse model of BA associated with situs inversus. Lectin histochemical methods for staining biliary epithelial cells in serial sections and methods for analyzing biliary excretion of radioisotopes were developed. The results show that these mice have proliferation of biliary ductules in the liver, complete interruption of the distal common bile duct and failure of technicium-labelled mebrofenin to be excreted from the liver in the bowel, providing evidence that inv mice do indeed have BA. In our most recent studies, we have identified in one inv mice do indeed have BA. In our most recent studies, we have identified in one inv mouse an anomaly of the common hepatic duct which resembles a choledochal cyst. In the studies proposed for this grant we will now characterize the spectrum of anomalies of bile duct development in inv mice; examine the morphogenesis of intrahepatic and extrahepatic bile ducts in wild type and inv mice during fetal development; and determine whether the action of the inv gene product has specific effects on bile duct morphogenesis.